Project Summary A major contributor to the development of obesity is compulsive eating with periods of abstaining from unhealthy eating habits but eventual relapse. This failure to self-regulate food intake has been attributed to the consumption of palatable foods that are highly rewarding, which reinforces compulsive feeding behavior. The cost on society of this health epidemic cannot be overstated and continues to grow. The nucleus accumbens (NAc) is a primary hub of the circuitry regulating motivation for food and has been extensively shown to be involved in other disorders with poor impulse control, notably addiction. This evidence makes the NAc a prime candidate region to investigate how the function of the brain?s reward circuity is impacted by chronic palatable food consumption. This proposal will employ a model of chronic limited-access high-fat intake to investigate the neural circuits regulating motivation to consume palatable food. The objectives of this proposal are to 1) identify neural circuits altered by chronic high-fat intake, with a focus on the NAc 2) establish the causative role of these neural circuits in the motivation to obtain high-fat through modulation of circuit activity, and 3) provide the applicant with the necessary intellectual and technical training to carry out an independent research program focused on elucidating the synaptic and neural circuit mechanisms underlying compulsive overeating. These objectives will be achieved using state of the art techniques, such as monosynaptic rabies tracing to map brain wide connectivity of specific cell types, in vivo calcium imaging of specific cell types and neural circuits, optogenetic modulation of circuit activity in sophisticated behavioral assays under the mentorship of leading experts in these techniques who are present at Stanford. Preliminary data demonstrate that chronic high-fat intake alters the intrinsic excitability of NAc neurons in a cell-type specific manner. Chronic high-fat also alters the synaptic strength at discrete inputs to NAc neurons, also in a cell-type specific manner. Furthermore, the population activity of a specific input to the NAc is increased during high-fat intake. Collectively these findings demonstrate the need for the proposed studies and likelihood that they will generate knowledge that will aid in the development of future therapeutic strategies for obesity. Moreover, this proposal will generate many new lines of inquiry for the applicant to pursue as an independent investigator.